1. Field of the Invention
The present invention relates to a sustained release pharmaceutical tablet of theophylline and a production process thereof. More specifically, it relates to a sustained release pharmaceutical tablet of theophylline containing a specified ratio of theophylline and ethyl cellulose and being prepared by a direct compression molding method.
2. Description of Prior Art
Theophylline is widely used as an effective medicament for therapy and prevention of bronchial asthma. The dosage of theophylline, however, must be strictly controlled, as is known in the art. This is because theophylline has a narrow range of effective concentration in blood (i.e., 5 to 20 .mu.g/ml) and gives rise to side-effects at the blood concentration (i.e., 25 .mu.g/ml or more) close to the range of effective blood concentration. These side effects include headaches, nausea and arrhythmia. Further, the biological half-life of theophylline is relatively short (i.e., about 6 hours). Theophylline must therefore be administered four times a day (i.e., every 6 hours) to maintain its effective concentration in the blood. Such a frequent dosage is very troublesome to patients. Also due to the short-half life, sufficient effect against asthma attack before dawn, the prime period for such attacks cannot be expected by theophylline administration before going to bed.
Various attempts have been made to develop sustained release theophylline pharmaceutical preparations to overcome the above problems. Several preparations have been proposed or marketed heretofore.
For example, U.S. Pat. Nos. 3,062,720, 3,402,240, and 3,456,049 disclose sustained, slow, or gradual release preparations or medicinal tablets comprising medicaments dispersed in matrices composed of substantially water-insoluble or slightly water-soluble fatty materials or waxes. U.S. Pat. Nos. 3,080,294, 3,109,775, 3,344,029, and 3,872,998 and Japanese Unexamined Patent Publication (Kokai) No. 56-122311 disclose sustained release pharmaceutical preparations comprising medicaments, in the form of beads having different release speeds, encapsuled in pellets, tablets, or capsules. Furthermore, U.S. Pat. Nos. 3,039,933, 3,322,633, and 3,632,739 disclose sustained release pharmaceutical tablets in which ethyl cellulose is contained as a portion of a matrix component, although the use of theophylline is not taught in these patent specifications.
Although these proposed sustained release preparations of theophylline alleviate the trouble in administration of theophylline, they do not eliminate it completely. That is, these sustained release theophylline preparations have an effective duration of 8 to 12 hours. Therefore, chronic bronchial asthmatic patients must still take these theophylline preparations two or three times a day in order to maintain the effective blood concentration. While better than that of conventional i.e., non-sustained release type theophylline preparations, this frequency is still greater than desired for chronic patients.
The above-mentioned preparations utilizing a water-insoluble (or slightly water-soluble) matrix still have disadvantages in that the weight percentage of the carrier or vehicle is as large as 50% or more. Thus, the size of the tablets inevitably becomes large in the case of a medicament, such as theophylline, which must be administered in a large dose. Also, the control of the release speed of the medicament is not necessarily easy since, depending upon the types or combinations of the matrix substances, the rate rapidly decreases with the lapse of time after administration.
Furthermore, the above-mentioned preparations utilizing coated beads (or small powder particles) also have disadvantages in that highly skilled art and complicated operations are required for the production of the coated beads, which cause high production costs.
Recently, a new type of a sustained release tablet of theophylline has been proposed in Japanese Unexamined Patent Publication (Kokai) No. 57-112322 (corresponding to U.S. patent application Ser. No. 147429 filed May 6, 1980). This proposed tablet comprises 95% to 99.8% by weight of theophylline in the form of a thin non-disintegration type flat plate. This tablet is advantageous in that its production is simple and it contains a large amount of the effective ingredient. It is still disadvantageous, however, in that a small sized tablet containing a small content (e.g., 50 to 150 mg) of theophylline has insufficient strength and too fast a release speed of the effective ingredient. Thus, a desired theophylline tablet having satisfactory sustained release properties and sufficient strength cannot be expected.